Title of Invention	PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF BACTERIAL AND PARASITIC INFECTIONS
Abstract	Pharmaceutical preparation comprising as activo agent a compound of the general formula (I) wherein R1 is selected from the group consisting of hydrogen end methyl, and wherein R2 and R3 are independently of each otirsr selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstitutcd iryl, substituted or unsubstituted aralkyl, substituted or - unsubstituted cycloalkyl, a substituted or unsubstituted silyl, substituted or unsubstitutcd heterocyclic radical, or jointly form a substituted or unsubstituted C1-5- alkytchain, wherein the alkyl groups are saturated or contain one or more double bonds or triple bonds, in combination with a socond pharmaceutical agent selected from the group consisting of clindamycin, lincomycin, pirlimycin and other lincosamides, azithromycin, erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, midecamycin, lumefantrine, tafenoquine (WR 238,605), pyronaridine, diliydroaitemisinin, artemether, arteether, artesunate.

Title of Invention

PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF BACTERIAL AND PARASITIC INFECTIONS

Abstract

Pharmaceutical preparation comprising as activo agent a compound of the general formula (I) wherein R1 is selected from the group consisting of hydrogen end methyl, and wherein R2 and R3 are independently of each otirsr selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstitutcd iryl, substituted or unsubstituted aralkyl, substituted or - unsubstituted cycloalkyl, a substituted or unsubstituted silyl, substituted or unsubstitutcd heterocyclic radical, or jointly form a substituted or unsubstituted C1-5- alkytchain, wherein the alkyl groups are saturated or contain one or more double bonds or triple bonds, in combination with a socond pharmaceutical agent selected from the group consisting of clindamycin, lincomycin, pirlimycin and other lincosamides, azithromycin, erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, midecamycin, lumefantrine, tafenoquine (WR 238,605), pyronaridine, diliydroaitemisinin, artemether, arteether, artesunate.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, Rule 13] PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF BACTERIAL AND PARASITIC INFECTIONS; BIOAGENCY AG A COMPANY ORGANISED AND EXISTING UNDER THE LAWS OF GERMANY WHOSE ADDRESS IS SCHNACKENBURGALLEE 116A, 22525 HAMBURG, GERMANY. THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. The present invention relates to pharmaceutical preparations comprising 3-N-formyl hydroxy amino propyl phosphonic acid de- • rivatives or 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives as active ingredients in combination with special pharmaceutical active ingredients: The use of 3-N-formyl hydroxy amino propyl phosphonic acid de-rivatives and 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives for prophylactic and therapeutic treatment of in-fectious processes, especially infections caused by unicellu-lar parasites (with the meaning of this invention: protozoa) or multicellular parasites, is already known from DE-A1-198 25 585. A bacterial activity has already been described in DE-A1-27 33 658. Even if these compounds exhibit good results in the treatment of infections caused by parasites or bacteria, also these medicaments exhibit undesired side-effects. Therefore, the present invention made it its object to enhance activity of these pharmaceutical preparations without increas-ing the side-effects of these active ingredients. Pharmaceuti-cal preparations shall be made available providing a reduction of side-effects. The object is as well to widen the range of therapeutic application of said pharmaceutical preparations and especially also to extend it to the treatment of problem-atic groups such as children, and pregnant women. The antipara-sitic activity shall be increased to such a degree such that these pharmaceutical preparations may be administered in lower doses and, thus, a reduction or elimination of side effects caused by these preparations is achieved. Surprisingly, it has been found that 3-N-formyl hydroxy amino propyl phosphonic acid derivatives and 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives in combination with a further pharmaceutical preparation being selected from the group .consisting of clindamycin, lincomycin, mirincamycin, pirlimycin and other lincosamides; minocycline and other tet¬racycline derivatives, azithromycin, erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, midecaraycin and other macrolide antibiotics, tiamuline, rifampicin, clotrim¬azole, flutrimazole, ketoconazole, tebuconazole, miconazole, itraconazole, fluconazole and other azole antimycotics; cipro¬floxacin, norfloxacin, ofloxacin and other inhibitors of pro-karyotic gyrase, nitrofurantoin, ornidazole, tinidazole, ni-morazole and other nitroimidazole derivatives; disulfiram and other dithiocarbamates; lumefantrine, tafenoquine (WR238,605), pyronaridine, dihydroartemisinin, artemether, arteether, arte-sunate, isoniazid, chlorproguanil, trimethoprim and tetroxo-prim, a significant higher therapeutic efficiency than in monotherapy. These combination preparations are especially suited for treatment of Malaria. According to the present invention 3-N-formyl-hydroxy amino propyl phosphonic acid derivatives and 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives are deeemed to be compounds of formula (I) (I) wherein Rx is selected from the group consisting of hydrogen and methyl, and wherein R2 and R3 are independently selected from the group, consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubsti- tuted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted si-lyl, substituted or unsubstituted heterocyclic residue, or to-gether form a substituted or unsubstituted C1-5-alkyl chain, the alkyl groups being saturated or comprising one or more double bonds or triple bonds. Lumefantrine, tafenoquine (WR238,605), pyronaridine, dihydro-artemisinin, artemether, arteether, artesunate, clindamycin and azithromycin are especially preferred for the second phar¬maceutical agent in the treatment of parasitic infections. Clindamycin and azithromycin are especially preferred in the treatment of bacterial as well as parasitic infections. The combination preparation of clindamycin or azithromycin is es¬pecially suited for the treatment of infections caused by Helicobacter pylori. The combination preparations are also deemed to be the respec¬tive salts, such as especially a fosmidomycin clindamycin salt and salts of other lincosamides. Special features of the above definitions and suitable exam¬ples thereof are stated below: "Acyl" is a substituent which originates from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioacid or imidic acid corresponding to the individual above-stated acids, or from an organic sulfonic acid, wherein these acids may in each case comprise aliphatic, aromatic and/or heterocyclic groups in the molecule, as well as car¬bamoyl or carbamimidoyl. Suitable examples of these acyl groups are stated below. Aliphatic acyl groups are deemed to comprise acyl residues originating from an aliphatic acid, such groups including the following: alkanoyl (for example formyl, acetyl, propionyl, butyryl, iso- butyryl, valeryl, isovaleryl, pivaloyl etc.); alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.); alkylthioalkanoyl (for example methylthioacetyl, ethylthioace- tyl etc.); alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesul- fonyl etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobu- toxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.); (N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.); alkylcarbamimidoyl (for example methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group or alkane residue, may optionally comprise one or more suitable sub-stituents, such as amino, halogen (for example fluorine, chlo¬rine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzyloxy etc.) and the like; preferred aliphatic acyl residues having such substituents which may be mentioned are alkanoyls substituted, for example, with amino, carboxy, amino and carboxy, halogen, acylamino or the like. Aromatic acyl residues are deemed to comprise those acyl resi¬due which originate from an acid with a substituted or unsub-stituted aryl group, wherein the aryl group may comprise phenyl, toluyl, xylyl, naphthyl and the like; suitable exam¬ples are stated below: aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phtha- loyl etc.); aralkanoyl (for example phenylacetyl etc.); aralkenoyl (for example cinnamoyl etc.); aryloxyalkanoyl (for example phenoxyacetyl etc.); arylthioalkanoyl (for example phenylthioacetyl etc.); arylaminoalJcanoyl (far example N-phenylglycyl etc.); arenesulfonyl (for example benzenesulfonyl, tosyl or toluene- sulfonyl, naphthalenesulfonyl etc.); aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycar- bonyl etc.); aralkoxycarbonyl (for example benzyloxycarbonyl etc.); arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.) In the above examples of acyl residues, the aromatic hydrocar¬bon moiety (in particular the aryl residue) and/or the ali¬phatic hydrocarbon moiety (in particular the alkane residue) may optionally comprise one or more suitable substituents, such as those which have already been stated as suitable sub¬stituents for the alkyl group or the alkane residue. Aromatic acyl residues having particular substituents which may in par¬ticular be mentioned and constitute examples of preferred aro¬matic acyl residues are aroyl substituted with halogen and hy¬droxy or with halogen and acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with arylthiocarbamoyl (for example phenylthiocarbamoyl etc.); arylcarbamimidoyl (for example phenylcarbamimidoyl etc.). A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acid with a heterocyclic group; these include: heterocyclic carbonyl, wherein the heterocyclic residue is an aromatic or aliphatic 5- to 6-tnembered heterocycle with at least one heteroatom from th4 group comprising nitrogen, oxy¬gen and sulphur (for example tjtitophenyl, furoyl, pyrrolocar-bonyl, nicotinoyl etc.); alkanoyl heterocycle, wherein the heterocyclic residue is 5-to 6-membered and comprises at least one heteroatom from the group comprising nitrogen, oxygen and sulphur (for example thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetra-zolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like. In the above examples of heterocyclic acyl residues, the het¬erocycle and/or the aliphatic hydrocarbon moiety may option¬ally comprise one or more suitable substituents, such as those as have been stated to be suitable for alkyl and alkane groups. "Alkyl groups™ are straight- or branched-chain alkyl residues having l to 24 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like. They may be e.g. substituted with hydroxy, halogen or oxy groups. Cycloalkyl preferably represents a optionally substituted C3.8-cycloalkyl; a. o. alkoxy (e.g. methoxy, ethoxy, etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like are suited to be possible substituents. Aryl is an aromatic hydrocarbon residue, such as phenyl, naph-thyl etc., which may optionally comprise one or more suitable substituents such as alkyl, alkoxy (for example methoxy, eth¬oxy etc.), trifluoromethylene, halogen (for example fluorine, chlorine, bromine etc.), nitro and the like. „Aralkyl" includes mono-, di-, triphenylalkyl such as benzyl, phenethyl, benzhydryl, trityl and the like wherein the aro- matic moiety may optionally comprise one or more suitable sub-stituents such as alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like. In the above ester the alkane and/or arene moiety may option¬ally comprise at least one suitable substituent, such as halo¬gen, alkoxy, hydroxy, nitro and the like. The invention further relates to the use of 3-N-formyl hydroxy amino propyl phosphonic acid derivatives or 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives in combination with clindamycin, lincomycin, mirincamycin, pirlimycin and other lincosamides, minocycline and other tetracycline derivatives, azithromycin, erythromycin, spiramycin, josamycin, roxithromy¬cin, clarithromycin, midecamycin and other macrolide antibiot¬ics, tiamuline, rifampicin, clotrimazole, flutrimazole, keto-conazole, tebuconazole, miconazole, itraconazole, fluconazole and other azole antimycotics, ciprofloxacin, norfloxacin, ofloxacin and other inhibitors of prokaryotic gyrase, nitrofu¬rantoin, ornidazole, tinidazole, nimorazole and other nitro-imidazole derivatives, disulfiram and other dithiocarbamates, lumefantrine, tafenoquine (WR238,605), pyronaridine, dihydro-artemisinin, artemether, arteether, artesunate, isoniazid, chlorproguanil, trimethoprim and tetroxoprim for therapeutic and prophylactic treatment of infections caused by bacteria, protozoa or multicellular parasites. The use of combination therapy with the help of pharmaceutical preparations of the present invention has the advantage of a synergistic increase of antiparasitic activity of the single substances. Hence, in combining the single compounds, there is a possibility of reducing the doses and, thus, the toxicity of the single compounds at the same time preserving antiparasitic activity. A combination therapy of the above listed principles of therapy of the individual coumpunds further provides the possibility of overcoming resistance. With the use of said combination therapy it is possible to ad¬minister the active agents in a so-called fixed combination, i.e. in a single pharmaceutical formulation containing both the active agents or to choose a so-called free combination, administering the active agents in form of separate pharmaceu¬tical formulations at the same time or one after the other. If the active agents are solid materials, the active agents may be administered by conventional methods for solid drug preparations mixing e.g. both active agents and pelletizing them for example into pellets together with conventional ex-cipients or auxiliary materials. However, it is also possible to provide the active agents separately in one package unit ready for sale wherein the package unit contains both active agents in separate pharmaceutical formulations. The pharmaceutical preparations may be administered in liquid or solid form for enteral or parenteral application. In this connection all conventional forms of application are possible, for example pellets, capsules, dragees, sirups, solutions, suspensions. Preferably, water is used as an injection medium containing added substances common in injection solutions such as stabilizers, dissolving intermediaries and buffers. If de¬sired, preparations suited for oral application may contain flavorings or sweeteners. The following example states the favourable activity of some representative combination preparations. The sensitivity of Plasmodium falciparum in view of fosmidomy-cin in combination with different compounds has been deter- mined in a semi-automatic test eystem by the incorporation of [3H]-hypoxanthin into the DNA of parasites. The IC50-values of fosmidomycin and the respective combination partner were de-termined for the single compounds and in different ratios of mixture on microtitreplates. The results were defined as sum of fractional inhibitory concentration (sum fractional inhibi-tory concentration, FIC): sum FIC = IC50 of fosmidomycin in mixture/IC50 of fosmidomycin alone + IC 50 of the combination partners in mix-ture/IC50 of combination partner alone Sum FlC-values l antargonism and values = 1 addition. It has to be considered that also slightly antargonistic combinations may be therapeutically valuable (sum FIC The following sum FIC-values have been measured on Plasmodium falciparum strains Dd2, 3D7 and HB3: drug P. falciparum strain sum FIC Dd2 0,42 clindamycin 3D7 0,40 HB3 0,37 Dd2 0,86 azithromycin 3D7 0,74 HB3 0,85 Dd2 1,20 lumefantrin HB3 1,08 3D7 1,21 We Claim I.. Pharmaceutical preparation comprising as activo agent a compound of the general formula (I) wherein R1 is selected from the group consisting of hydrogen end methyl, and wherein R2 and R3 are independently of each otirsr selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstitutcd iryl, substituted or unsubstituted aralkyl, substituted or - unsubstituted cycloalkyl, a substituted or unsubstituted silyl, substituted or unsubstitutcd heterocyclic radical, or jointly form a substituted or unsubstituted C1-5- alkytchain, wherein the alkyl groups are saturated or contain one or more double bonds or triple bonds, in combination with a socond pharmaceutical agent selected from the group consisting of clindamycin, lincomycin, pirlimycin and other lincosamides, azithromycin, erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, midecamycin, lumefantrine, tafenoquine (WR 238,605), pyronaridine, diliydroaitemisinin, artemether, arteether, artesunate. 2. Pharmaceutical preparation according to claim 1, - characterized in that, the second pharmaceutical agent is selected from the group consisting of lumetantrine, tafenoquine (WR 238,605), pyronaridine, dmydroartemisinin, artemether, arteether, artesunate.

Full Text

FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
& THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, Rule 13]
PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF BACTERIAL AND PARASITIC INFECTIONS;
BIOAGENCY AG A COMPANY ORGANISED AND EXISTING UNDER THE LAWS OF GERMANY WHOSE ADDRESS IS SCHNACKENBURGALLEE 116A, 22525 HAMBURG, GERMANY.
THE FOLLOWING SPECIFICATION
PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

The present invention relates to pharmaceutical preparations comprising 3-N-formyl hydroxy amino propyl phosphonic acid de- • rivatives or 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives as active ingredients in combination with special pharmaceutical active ingredients:
The use of 3-N-formyl hydroxy amino propyl phosphonic acid de-rivatives and 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives for prophylactic and therapeutic treatment of in-fectious processes, especially infections caused by unicellu-lar parasites (with the meaning of this invention: protozoa) or multicellular parasites, is already known from DE-A1-198 25 585. A bacterial activity has already been described in DE-A1-27 33 658. Even if these compounds exhibit good results in the treatment of infections caused by parasites or bacteria, also these medicaments exhibit undesired side-effects.
Therefore, the present invention made it its object to enhance activity of these pharmaceutical preparations without increas-ing the side-effects of these active ingredients. Pharmaceuti-cal preparations shall be made available providing a reduction of side-effects. The object is as well to widen the range of therapeutic application of said pharmaceutical preparations and especially also to extend it to the treatment of problem-atic groups such as children, and pregnant women. The antipara-sitic activity shall be increased to such a degree such that these pharmaceutical preparations may be administered in lower doses and, thus, a reduction or elimination of side effects caused by these preparations is achieved.

Surprisingly, it has been found that 3-N-formyl hydroxy amino propyl phosphonic acid derivatives and 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives in combination with a further pharmaceutical preparation being selected from the group .consisting of clindamycin, lincomycin, mirincamycin, pirlimycin and other lincosamides; minocycline and other tet¬racycline derivatives, azithromycin, erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin, midecaraycin and other macrolide antibiotics, tiamuline, rifampicin, clotrim¬azole, flutrimazole, ketoconazole, tebuconazole, miconazole, itraconazole, fluconazole and other azole antimycotics; cipro¬floxacin, norfloxacin, ofloxacin and other inhibitors of pro-karyotic gyrase, nitrofurantoin, ornidazole, tinidazole, ni-morazole and other nitroimidazole derivatives; disulfiram and other dithiocarbamates; lumefantrine, tafenoquine (WR238,605), pyronaridine, dihydroartemisinin, artemether, arteether, arte-sunate, isoniazid, chlorproguanil, trimethoprim and tetroxo-prim, a significant higher therapeutic efficiency than in monotherapy. These combination preparations are especially suited for treatment of Malaria.
According to the present invention 3-N-formyl-hydroxy amino propyl phosphonic acid derivatives and 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives are deeemed to be compounds of formula (I)
(I)
wherein Rx is selected from the group consisting of hydrogen
and methyl,
and
wherein R2 and R3 are independently selected from the group,
consisting of hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted acyl, substituted or unsubsti-

tuted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted si-lyl, substituted or unsubstituted heterocyclic residue, or to-gether form a substituted or unsubstituted C1-5-alkyl chain, the alkyl groups being saturated or comprising one or more double bonds or triple bonds.
Lumefantrine, tafenoquine (WR238,605), pyronaridine, dihydro-artemisinin, artemether, arteether, artesunate, clindamycin and azithromycin are especially preferred for the second phar¬maceutical agent in the treatment of parasitic infections.
Clindamycin and azithromycin are especially preferred in the treatment of bacterial as well as parasitic infections. The combination preparation of clindamycin or azithromycin is es¬pecially suited for the treatment of infections caused by Helicobacter pylori.
The combination preparations are also deemed to be the respec¬tive salts, such as especially a fosmidomycin clindamycin salt and salts of other lincosamides.
Special features of the above definitions and suitable exam¬ples thereof are stated below:
"Acyl" is a substituent which originates from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioacid or imidic acid corresponding to the individual above-stated acids, or from an organic sulfonic acid, wherein these acids may in each case comprise aliphatic, aromatic and/or heterocyclic groups in the molecule, as well as car¬bamoyl or carbamimidoyl.
Suitable examples of these acyl groups are stated below.
Aliphatic acyl groups are deemed to comprise acyl residues originating from an aliphatic acid, such groups including the

following:
alkanoyl (for example formyl, acetyl, propionyl, butyryl, iso-
butyryl, valeryl, isovaleryl, pivaloyl etc.);
alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.);
alkylthioalkanoyl (for example methylthioacetyl, ethylthioace-
tyl etc.);
alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesul-
fonyl etc.);
alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobu-
toxycarbonyl etc.);
alkylcarbamoyl (for example methylcarbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl
etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.);
oxalo;
alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl
etc
In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particular the alkyl group or alkane residue, may optionally comprise one or more suitable sub-stituents, such as amino, halogen (for example fluorine, chlo¬rine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzyloxy etc.) and the like; preferred aliphatic acyl residues having such substituents which may be mentioned are alkanoyls substituted, for example, with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Aromatic acyl residues are deemed to comprise those acyl resi¬due which originate from an acid with a substituted or unsub-stituted aryl group, wherein the aryl group may comprise phenyl, toluyl, xylyl, naphthyl and the like; suitable exam¬ples are stated below:

aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phtha-
loyl etc.);
aralkanoyl (for example phenylacetyl etc.);
aralkenoyl (for example cinnamoyl etc.);
aryloxyalkanoyl (for example phenoxyacetyl etc.);
arylthioalkanoyl (for example phenylthioacetyl etc.);
arylaminoalJcanoyl (far example N-phenylglycyl etc.);
arenesulfonyl (for example benzenesulfonyl, tosyl or toluene-
sulfonyl, naphthalenesulfonyl etc.);
aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycar-
bonyl etc.);
aralkoxycarbonyl (for example benzyloxycarbonyl etc.);
arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl
etc.);
arylglyoxyloyl (for example phenylglyoxyloyl etc.)
In the above examples of acyl residues, the aromatic hydrocar¬bon moiety (in particular the aryl residue) and/or the ali¬phatic hydrocarbon moiety (in particular the alkane residue) may optionally comprise one or more suitable substituents, such as those which have already been stated as suitable sub¬stituents for the alkyl group or the alkane residue. Aromatic acyl residues having particular substituents which may in par¬ticular be mentioned and constitute examples of preferred aro¬matic acyl residues are aroyl substituted with halogen and hy¬droxy or with halogen and acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, together with
arylthiocarbamoyl (for example phenylthiocarbamoyl etc.); arylcarbamimidoyl (for example phenylcarbamimidoyl etc.).
A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acid with a heterocyclic group; these include:
heterocyclic carbonyl, wherein the heterocyclic residue is an

aromatic or aliphatic 5- to 6-tnembered heterocycle with at least one heteroatom from th4 group comprising nitrogen, oxy¬gen and sulphur (for example tjtitophenyl, furoyl, pyrrolocar-bonyl, nicotinoyl etc.);
alkanoyl heterocycle, wherein the heterocyclic residue is 5-to 6-membered and comprises at least one heteroatom from the group comprising nitrogen, oxygen and sulphur (for example thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetra-zolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.
In the above examples of heterocyclic acyl residues, the het¬erocycle and/or the aliphatic hydrocarbon moiety may option¬ally comprise one or more suitable substituents, such as those as have been stated to be suitable for alkyl and alkane groups.
"Alkyl groups™ are straight- or branched-chain alkyl residues having l to 24 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like. They may be e.g. substituted with hydroxy, halogen or oxy groups.
Cycloalkyl preferably represents a optionally substituted C3.8-cycloalkyl; a. o. alkoxy (e.g. methoxy, ethoxy, etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like are suited to be possible substituents.
Aryl is an aromatic hydrocarbon residue, such as phenyl, naph-thyl etc., which may optionally comprise one or more suitable substituents such as alkyl, alkoxy (for example methoxy, eth¬oxy etc.), trifluoromethylene, halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.
„Aralkyl" includes mono-, di-, triphenylalkyl such as benzyl, phenethyl, benzhydryl, trityl and the like wherein the aro-

matic moiety may optionally comprise one or more suitable sub-stituents such as alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.
In the above ester the alkane and/or arene moiety may option¬ally comprise at least one suitable substituent, such as halo¬gen, alkoxy, hydroxy, nitro and the like.
The invention further relates to the use of 3-N-formyl hydroxy amino propyl phosphonic acid derivatives or 3-N-acetyl hydroxy amino propyl phosphonic acid derivatives in combination with clindamycin, lincomycin, mirincamycin, pirlimycin and other lincosamides, minocycline and other tetracycline derivatives, azithromycin, erythromycin, spiramycin, josamycin, roxithromy¬cin, clarithromycin, midecamycin and other macrolide antibiot¬ics, tiamuline, rifampicin, clotrimazole, flutrimazole, keto-conazole, tebuconazole, miconazole, itraconazole, fluconazole and other azole antimycotics, ciprofloxacin, norfloxacin, ofloxacin and other inhibitors of prokaryotic gyrase, nitrofu¬rantoin, ornidazole, tinidazole, nimorazole and other nitro-imidazole derivatives, disulfiram and other dithiocarbamates, lumefantrine, tafenoquine (WR238,605), pyronaridine, dihydro-artemisinin, artemether, arteether, artesunate, isoniazid, chlorproguanil, trimethoprim and tetroxoprim for therapeutic and prophylactic treatment of infections caused by bacteria, protozoa or multicellular parasites.
The use of combination therapy with the help of pharmaceutical preparations of the present invention has the advantage of a synergistic increase of antiparasitic activity of the single substances. Hence, in combining the single compounds, there is a possibility of reducing the doses and, thus, the toxicity of the single compounds at the same time preserving antiparasitic activity. A combination therapy of the above listed principles

of therapy of the individual coumpunds further provides the possibility of overcoming resistance.
With the use of said combination therapy it is possible to ad¬minister the active agents in a so-called fixed combination, i.e. in a single pharmaceutical formulation containing both the active agents or to choose a so-called free combination, administering the active agents in form of separate pharmaceu¬tical formulations at the same time or one after the other.
If the active agents are solid materials, the active agents may be administered by conventional methods for solid drug preparations mixing e.g. both active agents and pelletizing them for example into pellets together with conventional ex-cipients or auxiliary materials. However, it is also possible to provide the active agents separately in one package unit ready for sale wherein the package unit contains both active agents in separate pharmaceutical formulations.
The pharmaceutical preparations may be administered in liquid or solid form for enteral or parenteral application. In this connection all conventional forms of application are possible, for example pellets, capsules, dragees, sirups, solutions, suspensions. Preferably, water is used as an injection medium containing added substances common in injection solutions such as stabilizers, dissolving intermediaries and buffers. If de¬sired, preparations suited for oral application may contain flavorings or sweeteners.
The following example states the favourable activity of some representative combination preparations.
The sensitivity of Plasmodium falciparum in view of fosmidomy-cin in combination with different compounds has been deter-

mined in a semi-automatic test eystem by the incorporation of [3H]-hypoxanthin into the DNA of parasites. The IC50-values of fosmidomycin and the respective combination partner were de-termined for the single compounds and in different ratios of mixture on microtitreplates. The results were defined as sum of fractional inhibitory concentration (sum fractional inhibi-tory concentration, FIC):
sum FIC = IC50 of fosmidomycin in mixture/IC50 of fosmidomycin alone + IC 50 of the combination partners in mix-ture/IC50 of combination partner alone
Sum FlC-values l antargonism and values = 1 addition. It has to be considered that also slightly antargonistic combinations may be therapeutically valuable (sum FIC The following sum FIC-values have been measured on Plasmodium falciparum strains Dd2, 3D7 and HB3:
drug P. falciparum strain sum FIC
Dd2 0,42
clindamycin 3D7 0,40
HB3 0,37
Dd2 0,86
azithromycin 3D7 0,74
HB3 0,85
Dd2 1,20
lumefantrin HB3 1,08
3D7 1,21

We Claim
I.. Pharmaceutical preparation comprising as activo agent a compound of the general formula (I)

wherein R1 is selected from the group consisting of hydrogen end methyl,
and
wherein R2 and R3 are independently of each otirsr selected from the group consisting
of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl,
substituted or unsubstitutcd iryl, substituted or unsubstituted aralkyl, substituted or
- unsubstituted cycloalkyl, a substituted or unsubstituted silyl, substituted or
unsubstitutcd heterocyclic radical, or jointly form a substituted or unsubstituted C1-5-
alkytchain, wherein the alkyl groups are saturated or contain one or more double
bonds or triple bonds,
in combination with a socond pharmaceutical agent selected from the group consisting
of
clindamycin, lincomycin, pirlimycin and other lincosamides,
azithromycin, erythromycin, spiramycin, josamycin, roxithromycin, clarithromycin,
midecamycin,
lumefantrine, tafenoquine (WR 238,605), pyronaridine, diliydroaitemisinin,
artemether, arteether, artesunate.
2. Pharmaceutical preparation according to claim 1,
- characterized in that,
the second pharmaceutical agent is selected from the group consisting of lumetantrine, tafenoquine (WR 238,605), pyronaridine, dmydroartemisinin, artemether, arteether, artesunate.

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Patent Number

228242

Indian Patent Application Number

IN/PCT/2002/01879/MUM

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

29-Jan-2009

Date of Filing

24-Dec-2002

Name of Patentee

BIOAGENCY AG

Applicant Address

SCHNACKENBURGALLEE 116A, 22525 HAMBURG, GERMANY.

Inventors:

#	Inventor's Name	Inventor's Address
1	HASSAN JOMAA	FRANKFURTER STRASSE 50, D-35392 GIESSEN, GERMANY.
2	JOCHEN WIESNER	ZUR KASTANIE 8, D-35394 GIESSEN, GERMANY.

PCT International Classification Number

A61K31/66 A61P31/00

PCT International Application Number

PCT/EP01/07140

PCT International Filing date

2001-06-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	100 30 781.7	2000-06-29	Germany